Garbrecht, U.S. Pat. No. 3,580,916 discloses a group of lysergic and 9,10-dihydrolysergic acid esters formed with various open chain and cyclic diols. The following structures summarize the disclosure in Garbrecht. ##STR1## wherein R.sup.2 is H, C.sub.1-3 alkyl, allyl or benzyl and R.sup.2 is C.sub.2 -C.sub.8 monohydroxyalkyl, C.sub.2-8 dihydroxyalkyl or C.sub.5-11 monohydroxycycloalkyl having from 5-8 ring carbons. The compounds are useful as serotonin antagonists, the patent stating that "In animals, the compounds act as neurosedatives... and are therefore useful in calming. . . . animals".
The R.sup.2 group in I or II when it is hydroxycycloalkyl is formed by the reaction of a dihydroxycycloalkane with an "activated" form of lysergic or dihydrolysergic acid. The following list of illustrative cycloalkyldiols is from Garbrecht.
cyclopentane-1,3-diol, PA0 cyclohexane-1,4-diol, PA0 5,5-dimethylcyclohexane-1,3-diol, PA0 2-ethylcyclopentane-1,3-diol, PA0 cycloheptane-1,2-diol, PA0 4-methylcycloheptane-1,2-diol, PA0 cyclooctane-1,5-diol, PA0 3-ethylcyclooctane-1,3-diol, PA0 4-isopropylcycloheptane-1,2-diol, PA0 3-propylcyclooctane-1,5-diol, PA0 3-isopropylcyclooctane-1,5-diol PA0 2-Hydroxycyclohexyl 1-methyl-8.beta.-9,10-dihydrolysergate succinate PA0 2-Hydroxycyclopentyl 1,6-diethylergoline-8.beta.-carboxylate hydrochloride PA0 2-Hydroxycycloheptylergoline 1-n-propyl-6-allyl-8.beta.-carboxylate sulfate PA0 2-Hydroxycyclohexyl 1-isopropyl-6-ethylergoline-8.beta.-carboxylate hydrobromide PA0 4-Hydroxycycloheptyl 1-allyl-6-ethylergoline-8.beta.-carboxylate tartrate and the like.
No compound in which R.sup.2 is C.sub.5-11 monohydroxyalkyl was actually prepared.
Recently, interest in the Garbrecht compounds was intensified by the finding that they had excellent peripheral serotonin antagonist activity against 5HT.sub.2 receptors, at the same time and at comparable dose levels lacking any activity, agonist or antagonist, with other receptors, particularly alpha.sub.1 receptors.
The most interesting compound was 1-isopropyl-6-methyl-8.beta.-(1-methyl-2-hydroxy)propoxycarbonyl-5R-ergoli ne in which in II R.sup.1 is isopropyl and R.sup.2 is 1-methyl-2-hydroxypropyl. 5R refers to the orientation of the C-5 hydrogen. The C-10 hydrogen is alpha--10R, and the beta orientation at C-8 is the same as in lysergic and 9,10-dihydrolysergic acid (R). Both these acids have a 6-methyl group. An alternate name for the above compound is 1-isopropyl-9,10-dihydrolysergic acid 1-methyl-2-hydroxypropyl ester.
Cohen et al. J.P.E.T., 227, 327 (1983) (Cohen I) reported that the above compound, given the code number LY53857, was a potent antagonist of vascular contraction to serotonin, which effect is mediated by 5HT.sub.2 receptors. The compound had minimal affinity for vascular alpha adrenergic, dopaminergic and histaminergic receptors (K.sub.dissoc. .perspectiveto.10.sup.-10 vs .about.10.sup.-5). Other papers on the pharmacologic properties of LY53857 include Cohen et al, J.P.E.T., 232, 770 (1985) (Cohen III); Harriet Lemberger et al., Life Sciences, 35, 71 (1984); Cohen, Drug Development Res., 5, 313 (1985), (Cohen IV). Cohen and Fuller, EPO 122,044, published 10-17-84 (Cohen V) covers the use of the open chain hydroxy alkyl esters of 1-alkyl-dihydrolysergic acid as peripheral 5HT.sub.2 receptor antagonists.
The above articles tend to be cumulative concerning the lack of effect of LY53857 on receptors other than 5HT.sub.2 receptors, particularly peripheral alpha.sub.2 receptors.
Among the other prior art references, the next most pertinent group is that which contains references which have a bearing on the problem of finding selective ergolines (those with only one agonist or antagonist receptor interaction), including the following references:
Berde, The Medical Journal of Australia Special Supplement, page 3 (1978), divides the ergot alkaloids into four groups on structural grounds. Table 1 on page 4 of this article illustrates again the great differences in pharmacological activity between the various ergot alkaloids, specifically those listed at the top of the Table. The lack of selectivity of these alkaloids is fully illustrated; each has multiple pharmacologic activities. Attention is particularly called to page 6 of Berde where there is a section entitled "Use in Migraine". This section discusses the uses of ergotamine and methysergide in the treatment of an on-going migraine and as a preventative. Of all the compounds in Table 1, page 6 only methysergide has a 1,000 (most active compound rating) in a single test (5HT receptor blockade). The lack of correlation between these activities and migraine treatment become apparent when one realizes that ergotamine, the drug of choice in treating migraine, is the most active compound only in pressor and emetic activity, and not in 5HT antagonism.
Fanciullaci et al., Headache, 16 226 (1974), finds that both ergotamine and methysergide are 5HT agonists at low concentrations but antagonistic at higher concentrations. The authors conclude that methysergide and ergotamine therapy of migraine is not anti-serotoninergic.
Calesnick et al., A.F.P., 125, 228 (1982), also concludes that serotonin receptor agonists are the most effective agents for the treatment of migraine.
Awouters writing in 5-Hydroxy Tryptamines in Peripheral Reactions, (Raven Press, N.Y., 1982) points out that the 5HT.sub.2 agonist activity of methysergide is responsible for some of the side effects encountered with the use of that drug. Attention is also called to page 74, last paragraph, wherein the author states that ". . . there is still much room for the development of compounds which specfically block 5-hydroxy tryptamine-induced responses at low doses and do not have intrinsic 5-hydroxy tryptamine-like actions at all".
The following references are in our view, less pertinent than the previous references as regards the use of ergolines in migraine, and to the role of serotonin in that disease.
Aellig, Euro. J. Clin. Pharm., 25, 759 (1983) describes experiments contrasting pizotifen (pizotyline --a tricyclic compound having a benzene and a thiophene ring attached to a central cycloheptane carrying a 4-N-methylpiperidine--presently on clinical trial for migraine) with ergotamine in producing vasoconstriction, with or without noradrenaline. The conclusion is that ergotamine and noradrenaline act together to constrict cranial arteries when ergotamine is given for a migraine attack.
Sulman, Headache, 17, 203 (1977) discusses the use of danitracene in preventing migraine attacks. The drug had antiserotonin, antihistamine and antidepressive affects. Side affects attributable to the drug are given in Table 5.
Amano, ibid, 22, 249 (1982) studied the cerebrovascular changes in patients with headache being treated with the antiserotonin drugs, methysergide and cyproheptadine (compound 6 page 203 of Sulman). The author concludes that administration of methysergide may result in stimulation of serotonergic receptors, although it is also an antiserotonin drug.
Lance et al., Brit. Med. J., 1970 (2) 237 (Lance I) describes a comparative clinical trial of five serotonin antagonists in migraine. Improvement rates were (Table 1): methysergide 64%, cyproheptadine 43%, placebo 32%, lysenyl 34%, methdilazine 45% and BC105 50%. The side effects were very high (Table 2). 24-35% (placebo only 12%). Lysenyl is N-D-6-methylisoergolenyldiethylcarbamide --diethylamide of isolysergic acid. The difference in improvement rate between it and methysergide, another ergoline carboxamide, again points out the fact that all ergolines are not alike. Vasoconstriction was one of the chief side effects of methysergide treatment. The occurrence of retroperitoneal fibrosis etc. as a methysergide side effect is discussed.
Saxena, ibid, 12 44 (1972) concludes that "[t]he results of the present study cast doubts on the assumption that the antimigraine drugs owe their therapeutic activity to their antiserotonin action". (Page 52). He believes that selective vasoconstriction is the key to the treatment of migraine.
Lance and Anthony, Proc. Aust. Assoc. Neurol., 7, 31 (1970) (Lance II) contains an expansion of the data in Lance I. The authors conclude that the effectiveness of antiserotonin agents in migraine depends on their exerting a serotonin agonist action in promoting arterial vasoconstriction.
Prusinski et al., Pol. J. Pharmacol. Pharm., 27, (Supp) 189 (1975) tested two antiserotonin drugs (neither an ergoline) in migraine. Both were 64% effective.
Four additional patents are being cited as examples of ergolines with a substituent on the indole nitrogen. U.S. Pat. No. 3,113,133, Hofmann et al., discloses and claims esters and amides carrying an indole N substituent such as a lower alkyl or alkenyl group or an aralkyl group. The compounds are said to be useful as serotonin antagonists, in treating inflammatory, arthritic and allergic diseases and in treating carcinoid syndrome.
U.S. Pat. No. 3,249,617, Hofman et al., covers (indole) N-alkyl or allyl lysergic acids, useful as intermediates.
U.S. Pat. No. 3,228,941, Bernardi et al., discloses and claims a group of (indole) N-methylergolines --amides, hydroxamides and amidines. The compounds are alleged to have oxytocic, adrenolytic, hypotensive, sedative and antienteraminic action.
U.S. Pat. No. 4,230,859 to Rucman discloses dihydrolysergic acid carrying a C.sub.1-5 alkyl group on the indole nitrogen useful as intermediates.
Finally ergolines actually used in the treatment of migraine include ergotamine, methysergide and ergonovine. Ergotamine is both a partial alpha-agonist and an alpha-antagonist. In the peripheral and central nervous systems, it is mainly an antagonist, but is a partial agonist in certain blood vessels. Ergonovine, sometimes used in the treatment of migraine, is a 5HT agonist, is a selective and fairly potent 5HT antagonist in smooth muscle, is a weak dopaminergic antagonist, and is a highly active 5HT antagonist in the uterus. Methysergide, sometimes used in migraine, has no oxytocic action, little or no action on alpha-receptors, but is a partial 5HT agonist in certain blood vessels and a very potent 5HT antagonist in the CNS. From a description of their properties, it is apparent that none of these is an ideal migraine drug.